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1. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Swan, Anna L, Schütt, Christine, Rozman, Jan, del Mar Muñiz Moreno, Maria, Brandmaier, Stefan, Simon, Michelle, Leuchtenberger, Stefanie, Griffiths, Mark, Brommage, Robert, Keskivali-Bond, Piia, Grallert, Harald, Werner, Thomas, Teperino, Raffaele, Becker, Lore, Miller, Gregor, Moshiri, Ala, Seavitt, John R, Cissell, Derek D, Meehan, Terrence F, Acar, Elif F, Lelliott, Christopher J, Flenniken, Ann M, Champy, Marie-France, Sorg, Tania, Ayadi, Abdel, Braun, Robert E, Cater, Heather, Dickinson, Mary E, Flicek, Paul, Gallegos, Juan, Ghirardello, Elena J, Heaney, Jason D, Jacquot, Sylvie, Lally, Connor, Logan, John G, Teboul, Lydia, Mason, Jeremy, Spielmann, Nadine, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Odfalk, Kristian F, Parkinson, Helen, Prochazka, Jan, Reynolds, Corey L, Selloum, Mohammed, Spoutil, Frantisek, Svenson, Karen L, Vales, Taylor S, Wells, Sara E, White, Jacqueline K, Sedlacek, Radislav, Wurst, Wolfgang, Lloyd, KC Kent, Croucher, Peter I, Fuchs, Helmut, Williams, Graham R, Bassett, JH Duncan, Gailus-Durner, Valerie, Herault, Yann, Mallon, Ann-Marie, Brown, Steve DM, Mayer-Kuckuk, Philipp, and Hrabe de Angelis, Martin

Subjects
Biological Sciences, Genetics, Aging, Osteoporosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Bone Density, Female, Gene Expression Regulation, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts, Osteoclasts, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, IMPC Consortium, Developmental Biology
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Published
2020

2. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Nutrition, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Published
2018

3. Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

Author

Ali Önder Yildirim, Valerie Gailus-Durner, Tim M. Strom, Susan Marschall, Michael A. Sandholzer, Wolfgang Wurst, Katharina Baron, Sibylle Sabrautzki, Eckhard Wolf, Martin Hrabě de Angelis, Jan Rozman, Robert Brommage, Claudia Stoeger, Birgit Rathkolb, Lillian Garrett, Sabine Hoelter, Christine Gau, Leuchtenberger Stefanie, Ingrid L. Vargas Panesso, Christoph Lengger, Martin Klingenspor, Lore Becker, Thomas Klopstock, Helmut Fuchs, Bettina Lorenz-Depiereux, Gerhard K. H. Przemeck, Alexandra Vernaleken, and Wolfgang Hans

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Genotype, Mutant, physiopathology [Mandibulofacial Dysostosis], genetics [Mandibulofacial Dysostosis], Mutagenesis (molecular biology technique), 030105 genetics & heredity, Biology, medicine.disease_cause, Article, genetics [Receptor, Endothelin A], Mice, 03 medical and health sciences, ddc:570, Genetics, medicine, Animals, Humans, Craniofacial, genetics [Alopecia], Mutation, physiopathology [Alopecia], Alopecia, Receptor, Endothelin A, medicine.disease, Endothelin 1, Phenotype, Human genetics, 030104 developmental biology, Dysplasia, Mandibulofacial Dysostosis, Signal Transduction
Abstract

Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra Y129F mice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)–endothelin receptor type A (EDNRA) signaling. Above all, Ednra Y129F mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions. Electronic supplementary material The online version of this article (doi:10.1007/s00335-016-9664-5) contains supplementary material, which is available to authorized users.

Published
2016
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4. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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5. Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

Author

Egaña, Isabel, Kaito, Hiroshi, Klopstock, Thomas, Fuchs, Helmut, Gailus-Durner, Valerie, Hrabe de Angelis, Martin, Rask-Andersen, Helge, Johansson, Henrik J, Lehtiö, Janne, He, Liqun, Yildirim, Ali Ö, Hellström, Mats, Nitzsche, Anja, Consortium, German Mouse Clinic, Aguilar-Pimentel, Antonio, Ollert, Markus, Schmidt-Weber, Carsten, Amarie, Oana, Graw, Jochen, Beckers, Johannes, Garrett, Lillian, Hölter, Sabine M, Zimprich, Annemarie, Becker, Lore, Wurst, Wolfgang, Moreth, Kristin, Bekeredjian, Raffi, Neff, Frauke, Calzada-Wack, Julia, Rácz, Ildikó, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Rozman, Jan, Ballester-Lopez, Carolina, Klingenspor, Martin, Stoeger, Tobias, Eickelberg, Oliver, Treise, Irina, Busch, Dirk H, Östereicher, Manuela, Steinkamp, Ralph, Lengger, Christoph, Maier, Holger, Stoeger, Claudia, Niaudet, Colin, Leuchtenberger, Stefanie, Petkova, Milena, Liu, Wei, Vanlandewijck, Michael, and Vernaleken, Alexandra

Subjects
Male, Heterozygote, lcsh:Medicine, Apoptosis, genetics [Emphysema], pathology [Endothelial Cells], Article, genetics [Phosphoprotein Phosphatases], Mice, Sex Factors, Phosphoprotein Phosphatases, Animals, Humans, lcsh:Science, Pald1 protein, mouse, Lung, pathology [Emphysema], metabolism [Phosphoprotein Phosphatases], Emphysema, Mice, Knockout, lcsh:R, growth & development [Endothelium, Vascular], Endothelial Cells, Embryo, Mammalian, Mice, Inbred C57BL, Disease Models, Animal, physiology [Apoptosis], lcsh:Q, Female, Endothelium, Vascular, blood supply [Lung], ddc:600
Abstract

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

Published
2017
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6. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

Author

Fuchs, Helmut, Sabrautzki, Sibylle, Przemeck, Gerhard K. H., Leuchtenberger, Stefanie, Lorenz-Depiereux, Bettina, Becker, Lore, Rathkolb, Birgit, Horsch, Marion, Garrett, Lillian, Östereicher, Manuela A., Hans, Wolfgang, Abe, Koichiro, Sagawa, Nobuho, Rozman, Jan, Vargas-Panesso, Ingrid L., Sandholzer, Michael, Lisse, Thomas S., Adler, Thure, Aguilar-Pimentel, Juan Antonio, Calzada-Wack, Julia, Ehrhard, Nicole, Elvert, Ralf, Gau, Christine, Hölter, Sabine M., Micklich, Katja, Moreth, Kristin, Prehn, Cornelia, Puk, Oliver, Racz, Ildiko, Stoeger, Claudia, Vernaleken, Alexandra, Michel, Dian, Diener, Susanne, Wieland, Thomas, Adamski, Jerzy, Bekeredjian, Raffi, Busch, Dirk H., Favor, John, Graw, Jochen, Klingenspor, Martin, Lengger, Christoph, Maier, Holger, Neff, Frauke, Ollert, Markus, Stoeger, Tobias, Yildirim, Ali Önder, Strom, Tim M., Zimmer, Andreas, Wolf, Eckhard, Wurst, Wolfgang, Klopstock, Thomas, Beckers, Johannes, Gailus-Durner, Valerie, and Hrabé de Angelis, Martin

Subjects
Male, mouse model, genetics [Energy Metabolism], QH426-470, Investigations, pleitropy, Kidney, Kidney Function Tests, Bone and Bones, metabolism [Bone and Bones], Mice, systemic phenotype, ddc:570, pathology [Osteitis Deformans], Genetics, Animals, physiopathology [Kidney], Exome, Genetic Association Studies, Skeleton, Glycoproteins, Mice, Knockout, metabolism [Osteitis Deformans], SCUBE3, Gene Expression Profiling, Calcium-Binding Proteins, metabolism [Kidney], Chromosome Mapping, High-Throughput Nucleotide Sequencing, Osteitis Deformans, abnormalities [Skeleton], Disease Models, Animal, genetics [Osteitis Deformans], Phenotype, Mutation, Scube3 protein, mouse, Female, genetics [Glycoproteins], Paget disease of bone (PDB), Energy Metabolism
Abstract

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3(N294K/N294K)), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3(N294K/N294K) mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3(N294K/N294K) mice. The Scube3(N294K/N294K) mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Published
2016
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7. AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease.

Author

Jacobs, Howard T., Szibor, Marten, Rathkolb, Birgit, da Silva-Buttkus, Patricia, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, Dragano, Nathalia, Garrett, Lillian, Gerlini, Raffaele, Hölter, Sabine M., Klein-Rodewald, Tanja, Kraiger, Markus, Leuchtenberger, Stefanie, Marschall, Susan, Östereicher, Manuela A., Pfannes, Kristina, Sanz-Moreno, Adrián, and Seisenberger, Claudia

Subjects
*MICE, *LABORATORY mice, *CIONA intestinalis, *ANIMAL disease models, *PHENOTYPES, *METABOLIC disorders
Abstract

The alternative oxidase, AOX, provides a by-pass of the cytochrome segment of the mitochondrial respiratory chain when the chain is unavailable. AOX is absent from mammals, but AOX from Ciona intestinalis is benign when expressed in mice. Although non-protonmotive, so does not contribute directly to ATP production, it has been shown to modify and in some cases rescue phenotypes of respiratory-chain disease models. Here we studied the effect of C. intestinalis AOX on mice engineered to express a disease-equivalent mutant of Uqcrh, encoding the hinge subunit of mitochondrial respiratory complex III, which results in a complex metabolic phenotype beginning at 4–5 weeks, rapidly progressing to lethality within a further 6–7 weeks. AOX expression delayed the onset of this phenotype by several weeks, but provided no long-term benefit. We discuss the significance of this finding in light of the known and hypothesized effects of AOX on metabolism, redox homeostasis, oxidative stress and cell signaling. Although not a panacea, the ability of AOX to mitigate disease onset and progression means it could be useful in treatment. [Display omitted] • Loss of complex III subunit Uqcrh is lethal in mice at ~9 weeks of age. • Causes post-weaning growth failure with metabolic disturbance • Expression of the alternative oxidase, AOX, delayed lethality by ~3 weeks. • AOX transiently ameliorated many phenotypic manifestations. • AOX is not a panacea but can delay onset/progression of respiratory chain disease. [ABSTRACT FROM AUTHOR]

Published
2023
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8. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
Male, Osteoporosis, genetics [Gene Expression Regulation], Transgenic, Transcriptome, Mice, 0302 clinical medicine, Animal Cells, Aetiology, Musculoskeletal System, Connective Tissue Cells, Genetics & Heredity, 0303 health sciences, Genomics, 3. Good health, Cellular Types, musculoskeletal diseases, Genotype, In silico, 1.1 Normal biological development and functioning, 03 medical and health sciences, genetics [Osteoporosis], Rheumatology, pathology [Osteoblasts], Genetic, Genome-Wide Association Studies, Genetics, GENOME-WIDE ASSOCIATION, Molecular Biology, Skeleton, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, metabolism [Osteoblasts], 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Osteoblasts, IDENTIFICATION, Biology and Life Sciences, Computational Biology, medicine.disease, COLLAGEN, Biological Tissue, OSTEOGENESIS IMPERFECTA, DISCOVERY, IMPC Consortium, Mutation, Animal Studies, Developmental Biology, Candidate gene, Cancer Research, Bone density, Gene Expression, Osteoclasts, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, Bone remodeling, Bone Density, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Protein Interaction Maps, Connective Tissue Diseases, Promoter Regions, Genetic, Genetics (clinical), Bone mineral, Sex Characteristics, genetics [Bone Density], metabolism [Osteoclasts], Genetic Pleiotropy, Animal Models, pathology [Osteoclasts], Phenotype, DIFFERENTIATION, Experimental Organism Systems, ANIMAL-MODELS, Connective Tissue, SEX, Female, Anatomy, Technology Platforms, Life Sciences & Biomedicine, Research Article, metabolism [Osteoporosis], Mouse Models, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, Research and Analysis Methods, Promoter Regions, Model Organisms, Underpinning research, medicine, Animals, ddc:610, Bone, 030304 developmental biology, Human Genetics, Cell Biology, Genome Analysis, Gene Ontology, Gene Expression Regulation, Musculoskeletal, Genome-Wide Association Study
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

Published
2021
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